1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to compositions comprising blockers of sodium (Na+) channels and at least one of gabapentin or pregabalin. The invention also relates to methods for the treatment of chronic pain or convulsions comprising coadministering a sodium channel blocker and at least one of gabapentin or pregabalin.
2. Related Background Art
Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and carbamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity (Catterall, W. A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na+ ions. Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J. Pharmacol. 115:1425-1432 (1995); SCRIP 1870:8 (1993); SCRIP 1773:14 (1992)).
The neuroprotective activity of Na+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that unlike glutamate receptor antagonists, Na+ channel blockers prevent hypoxic damage to mammalian white matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
Another example of clinical use of a Na+ channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76 (1994)).
It has been established that there are at least five to six sites on the voltage-sensitive Na+ channels which bind neurotoxins specifically (Catterall, W. A., Science 242:50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na+ channel and allosterically inhibiting interaction with neurotoxin receptor site 2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)).
Chronic pain or neuropathic pain is a heterogenous disease state with an unclear etiology. In chronic pain, the pain can be mediated by multiple mechanisms. This type of pain generally arises from injury to the peripheral or central nervous tissue. The syndromes include pain associated with spinal cord injury, multiple sclerosis, post-herpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia and reflex sympathetic dystrophy and lower back pain. The chronic pain is different from acute pain in that patients suffer the abnormal pain sensations that can be described as spontaneous pain, continuous superficial burning and/or a deep aching pain. The pain can be evoked by heat-, cold- and mechano-hyperalgesia or by heat-, cold- and mechano-allodynia (International association for the study of pain: The classification of chronic pain (1995); Bennett G. J. Molecular Neurobiology of Pain, Progress in Pain Research and Management Vol. 9, pp. 109-113, edited by D. Borsook, 1997). In most cases, chronic neuropathic pain responds poorly to treatment with opiates or nonsteroidal anti-inflammatory analgesia.
Carbamazepine (Tegretol™), a sodium channel blocker anticonvulsant, has been shown to be effective in trigeminal neuralgia. However, one third of patients cannot tolerate the drug in the dose required to alleviate the pain (Victor et al., Harrison's Principles of Internal Medicine. 11th ed. New York: McGraw-Hill 1987; 2035-40). In addition, carbamazepine may cause aplastic anemia, agranulocytosis, and hypersensitivity reaction (Canavero et al., Pain 60:229-31 (1995)). These serious side effects are dose related. Carbamazepine is the only drug approved by the FDA for this indication.
There are no other drugs thus far that have been approved for chronic pain. Lamotrigine (Lamictal) is a sodium channel blocker that has been approved by the FDA for treating convulsions. This drug has also been shown to be effective for treating chronic pain (Lundardi et al., Neurology 48: 1714 (1997)). However, the doses required for the treatment of chronic pain are relatively high and result in side effects. The major side effect of this drug is severe, potentially life-threatening rashes (Dichter and Brodie, New Engl. J. Med. 334: 1583 (1996)).
Gabapentin (Neurontin™), an anticonvulsant with unknown mechanism of action has been shown recently to be efficacious for treating chronic pain (Rowbotham et al., JAMA 280: 1837-1842 (1998) and Backonja et al., JAMA 280: 1831-1836 (1998)). However, higher doses are necessary to treat chronic pain. Side effects such as exacerbated absence seizures and nausea are associated with these high doses in addition to being fetotoxic. In addition, in clinical trials, gabapentin showed limited efficacy (i.e., less than 50% of patient population showed effectiveness, whereas 15-20% of patients treated with placebo showed effectiveness).
Pregabalin is a potent follow-up compound to gabapentin. The compound has similar activity to gabapentin and is currently under clinical trials for neuropathic pain (SCRIP 2330:8 (1998)).
Thus, a need exists for treatments of chronic pain and convulsions that avoid the side effects exhibited by lamotrigine, carbamazepine and gabapentin. The present invention provides compositions and methods which reduces such side effects and improves the response rate of patients.